Myelokathexis in an 18‐year‐old male patient with severe neutropenia and lymphopenia
Authors: Endi Wang, Yue Zhao, Sophie Parks, Imran Siddiqi
Journal: American Journal of Hematology (2023)

An 18-year-old male patient presented to clinic with an episode of self-inflicted injury. Routine laboratory evaluation with complete blood count demonstrated severe leukopenia to 0.9 × 109/L (0.1 × 109/L neutrophils, 0.3 × 109/L lymphocytes) with normal levels of hemoglobin (141 g/L) and platelets (238 × 109/L). Lymphocyte enumeration demonstrated that B-cells accounted for 1.8% of total leukocytes (normal reference, 6.9%–14.9%), though his serum immunoglobulin profile was within normal range. He was asymptomatic and denied previous history of warts or recurrent infections except for a recent episode of scrotal abscess with mixed bacterial growth that resolved with drainage and antibiotics. Bone marrow examination was performed to evaluate the etiology of severe leukopenia. Review of the peripheral blood smear confirmed severe neutropenia and lymphopenia without circulating blasts. Bone marrow aspirate smear exhibited trilineage hematopoiesis with myeloid to erythroid (M:E) ratio of 2:1. Interestingly, granulopoiesis appeared to be right-shifted with many mature neutrophils displaying elongated thin filamentous connection between nuclear lobes, a feature suggestive of myelokathexis (Image 1). Significant dysplasia or increase in blasts was not otherwise identified. Cytogenetic studies were negative for abnormalities. Next generation sequencing analysis demonstrated frameshift mutation in CXCR4 with variant allele frequency (VAF) of 50%, and missense mutation of CSF3R with VAF of 49.8%. Given the clinical presentation, bone marrow morphology and molecular testing, the diagnosis of WHIM syndrome was established. Unfortunately, a test for hereditary CXCR4 mutation was not able to be performed in the parent, even though the VAF was highly suggestive of a germline mutation rather than a somatic event. Following the diagnosis, the patient began regular surveillance for leukopenia and opportunistic infections. The acronym WHIM is derived from the main features of the disease, which include Warts, Hypogammaglobulinemia, Infection, and Myelokathexis.1 Of these, myelokathexis refers to the abnormal retention of mature neutrophils in bone marrow, and is considered to be a pathognomonic finding for WHIM syndrome.2 The disease is an immunodeficiency disorder of autosomal dominant inheritance caused by germline mutations in CXCR4, which encodes a chemokine receptor. The pathogenesis of WHIM syndrome is mediated by gain of function mutation of CXCR4, resulting in increased response to its unique ligand CXCL12. The altered CXCR4/CXCL12 interaction likely impairs cellular homeostasis and trafficking, leading to immunological dysfunctions.3 WHIM patients often suffer from recurrent bacterial infections since childhood and show marked susceptibility to infection by human papilloma virus. Hematological manifestations usually include neutropenia, lymphopenia and hypogammaglobulinemia. However, the majority of the patients, including the one in this case, manifest an incomplete phenotype at the onset, leading to the diagnosis of WHIM to be often overlooked.1, 3 Identification of myelokathexis may prompt a subsequent genomic analysis resulting in early diagnosis of WHIM syndrome and timely clinical management of the disease before complications arise. Such management includes G-CSF-induced granulocytic production and mobilization, immunoglobulin supplementation, antibiotic prophylaxis and specific antagonists targeting the underlying molecular pathogenesis: CXCR4 hyperfunction (plerixafor). Imran Siddiqi organized the study and edited the manuscript. Sophie Parks edited the manuscript. Yue Zhao prepared the images and edited the manuscript. Endi Wang organized the study and wrote the manuscript. The authors declare no conflicts of interest. Data sharing is not applicable to this article as no new data were created or analyzed in this study.